In technical fields relating to chemical formulation of compounds, such as, but not limited to the fields of pharmaceutical and agrochemical research and development, it is frequently necessary to evaluate the general suitability of a newly developed active pharmaceutical ingredient (API) candidate prior to launching into full development. Such an evaluation of the general suitability or, in the field of pharmaceutical development, therapeutic effectiveness of such chemical compounds typically includes solubility studies of the compound in various solvents as well as solubility profiles at various pH values.
However, carrying out such studies for a great many compounds can be problematic and resource-intensive. At the earlier stages of the drug discovery process, in particular, the solubility measurements are generally performed for a large variety of compounds. Furthermore, many of these compounds are only available in limited quantities, either due to difficulties in manufacturing larger quantities or simply because the cost of producing or handling larger quantities of the compounds is not feasible.
However, simply bypassing the solubility studies is also not a viable option for product development as selection of an otherwise suitable candidate compound that does not have a suitable solubility profile can cause significant problems. Indeed, insoluble or poorly soluble compounds often prove difficult to develop into drugs. Even with significant motivation, the development of low-solubility drugs is more time-consuming and expensive than for a compound with otherwise more suitable properties. Traditionally, “equilibrium” solubility has been determined by agitating or shaking the compound with the solvent of choice for at least 24 hours or until no more of the compound will dissolve, then filtering, and determining the concentration of dissolved compound by a suitable analytical assay. These analytical assays have to be calibrated, a process which includes preparation of at least several solutions of known varied concentrations of the compound (standard solutions), and establishing a quantitative relationship between a measurable analytical signal and the compound concentration. This approach is inappropriate in a modern drug discovery setting. The throughput, or number of unknown samples that can be determined in a given amount of time, and using a given quantity of resources, such as machines, personnel, samples, and the like, is insufficient to meet the required demand to analyze a great number of potential lead compounds. For example, determination of the mass of samples and/or standards presents too restrictive a checkpoint in the process for maintaining the high throughput desired as the process demands weighing hundreds (or thousands) of solid samples in submilligram quantities.
The present invention provides new methods for the measurement of concentration and solubility of an API in a multi-component system without the need of preparing a plurality of standard samples with a distribution of well-defined concentrations or the generation of a traditional calibration curve.
The present invention also provides methods of determining the saturation concentration (Csat) of a solute in a polymer matrix or a polymer matrix film. In order to find the saturation concentration of a solute in a polymer network, it is often necessary to titrate a series of formulations and then to wait for long periods of time for the solute in supersaturated systems to diffuse, form a critical nucleus and grow. The formulations are visually observed after a given period and the solubility is estimated. This method can lead to over-estimated solubility limits since it can take weeks, months, or years before crystallization occurs in some systems. The induction time depends on factors such as the glass transition temperature of the polymer, the size of the permeant, the temperature, and the concentration driving force. In a titration series, the formulations closest to, but still above, the solubility limit will take the longest time to crystallize since the driving force is low.